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A new method for establishment of absolute configurations of secondary alcohols by NMR spectroscopy
Te&zkdrooLuters, Vol. 35. No. 4, p. 599-602 1994 Elsevia ScienceL.&i RimedinGrea~Britaia 0040-4039194 [email protected]
A NEW MEXHOD FOR ESTABLISHMENT OF ABSOLUTE CONFIGURATIONS OF SECONDARY ALCOHOLS BY NMR SPECTROSCOPY
Yukiharu Fukushi*,
Cbie Yajima and Juaya Mizutani
Departmentof Applied Bioscience, Faculty of Agriculture,HokkaidoUniversity, Kita-ku, Sapporo 060, Japan
Abstrnet : Axially chiral T-methoxy-i,l’-binaphtbyl-Z- carboxylicackt{MBNC, 2) aad Z-(~-metboxy-i’-naphthyl~ 3,5-dichlorobenzoicacid (MNCB, 3) were uscd as chiml derivatiziig agents to determineabsolute ~onfigumtionsof secondaryalcohols by 1~ and 1% NMR spectroscopy.
Recently cwfigurations
a number
of chiml derivatizing
and entmtiomtziic purities
C-centrochirdlity,
agents have been developed
of optically
active mmpoundsl.
for feting
Almost
and among of them, Mosher’s a-methoxy-u-trifluoromethyhylphenylaoetic
absolute
all of them possess acid (MTF’A, 1) has
been most widely used2. “Modified Masher’s method”, a modem variation of Masher’s (lH) method improved by Ohtani et al., is applicable to general secondary alcohols except sterically hindered ones3. On the other hand, Miyano ti al. pointed out the utility of axially chiml 2’-methoxy-l,l’-binaphthyl-2~r~xylic as derivatizing agent for dis~~ation
acid (MBNC, 2)
of emmtiomeric alcohols and amines by ‘H NMR with the aid of
Eu(fod)J”, We estimated dichlorobenzoic
that
axially
chiral
carboxylic
acids
like
2
and
2-(2’-methoxy-l’-naphthyl)-3,5-
acid (MNCB, 3) would be more versatile agents than MlTA
for Musher’s (lH) method.
Enantiomers of 2 were prepared by a known method 5. Racemic 3 was prepared following the procedure of Hotta ef al.“, and derivatized into d~~tereome~c esters of (~}-l-~~nethoI silica-gel column chromatography.
which were separatedeach other by
Purified diastereomers were respectively hydrolyzed by alkali to yield (&)-
and +1&‘)-3~.Various secondary alcohols (4-16) were esterified with (I@- and (a‘Q8-2, and (a@- and (sS)-3 by DCC and 4-pyrrolidinopyridine9.
On the basis of ‘H NMR analyses of the respective diastereomers and the
X-ray crystallographic
data of (a.S)- 2 ester of (-)-mentho17, we devised a new method that could predict the
absolute ~)~igurations
of the chiml secondary alcohols ~cluding sterimlly hindered ones. The basic concept of
this method is essentially the same as that uf “modified Musher’s methud”. For explanation of this method, hereinafter MNI3B esters m used. The idealized conformation
of MNCB
esters is depicted in Figure 1A. 1) The carbinyl proton, ester carbonyl and benzene ring of MNCB moiety lie in the same plane, and the alcohol moiety is neaf the naphthalene ring. 2) The naphthalene and the benz.ene rings of MNCB moiety are orthogonal. For convenience, the plane containing the benzene ring and the conformation of the MNCB group are named tbe CB plane and the ideal ~nfo~tion,
respectively. Due to the d&magnetic
effect of the naphthalene ring, the Ha, Ha’, Hb and Hb’ NMR signals of MNCB ester should appear upfield relative to those of the original alcohol, and also the Ha signal of the (aR)-MNCB ester should appear upfield 599
Hb
Ha
(aS)-MNCE
Hb
estar
(a&MNc8
astar
Figure 1. (A) Cmfigurdtimal correlation mode1 for the (aS)-MNCB
derivatives. CB and border planes are shown. Ha and Hb are on the left and right sides of the CB plane, respectively. Ha’, Hb’ and catbitryl proton are under the border plane. (B) and (C) Views of the (aS)- and (aR)-MNCE esters drown from the direction shown by the outlined arrow in (A).
relative to that of the (as)-MNCB
ester. The reverse should hold true for Hb (Figure 1B). Therefore, when chemical shift difference is defined as Ali(ppm)=GaF - 8&t@, protons on the left side of the CB plane must have positive values (A&O) and protons on the right side of the plane must have negative values (A&CO). The principle is illustrated in Sgure
1B and 1C. The plane, which contains
1’ and 8’ carbons of the naphthakne
ring and the alkoxy oxygen, is drawn with a dotted line in Figure lA-C, This plane is named the border plane. A8 values of the protons under the border plane (Ha’, Hb’ and the carbinyi) am unpredictable, because these protons are strongly irreguk
affected by a fine deviation from the ideal conformation.
However
the signs of AhBof
protons are apt to be the same as that of the car-vinyl proton‘s 116. When these conditions
model A will indicate the correct absolute configuration
are satisfied,
of the compound in question.
As an example, (-)-menthol derivatives (16) can be used to demonstrate the validity of the present method (Figure 2 and Table 1). It is evident that the individual proton signal of the alcohol moieties of MNCB esters appears in upper field than the corresponding one of the original alcohol except the carbinyi proton. Especially, 2fi proton signals of (aS)- and (a@MNCB esters appear at 0.13 and -0.23ppm, respectively. The protons with Ab>O am located on the left side of the CB plane and the ones with AS<0 on the right side. Also, A& values ate infhtenced by the distance between the protons and the ~hth~ene ring. Cto methyl protons, which may be under the border plane (16’), show positive A6 value but the sign is the same as that of the carbinyl proton. This correlation also holds in MBNC esters (4, MBNC esters of (-)-menthol was determined.
9, 16) in Figure 2. By comparison
in ‘H MNR (Table l), the absolute configuration
between
of each enantiomer
MNCB and of MNCB
601
Table
1. lH NMR Data of (-)-Menthol and its MNCB and MBNC Esters {16).
Position
1
2a
R=H MNCEl(aR) (as) MBNC(aS) laRl
1.42 1.16 1.22 1.18 1.26
1.96 1.26 1.48 1.34 1.62
2% 0.95 -0.23 0.13 -0.23 0.24
3
4
5a
3.41 4.40 4.44 4.48 4.52
1.11 0.63 0.41 0.68 0.44
0.99 0.78 0.77 0.82 0.80
5% 1.61 1.43 1.39 1.44 1.40
6a 1.66 1.47 1.49 1.50 1.53
6% 0.84 0.52 0.54 0.54 0.58
7 0.93 0.64 0.73 0.64 0.76
9
8 2.17 1.33 1.11 1.45 1.12
0.91 0.68 0.50 0.71 0.48
10 0.81 0.42 0.46 0.49 0.47
R = ii,YNCB, MBNC
Figure 2 A6 values in 1H: NMR obtained for the MNCB and MBNC esters of secondary alcohols. The values in the parentheses are A& of MBNClob esters. Border planes are shown by dotted lines. For consistency, the results have been transposed to one enantiomer of alcohol (ex. (a.S, R ) = (al?, S)). 16' shows possible ~~~atio~ of 16 (R = MNCB and MBNC). This method is applicable to sterically hindered alcohols (12, 14), and iu t3C NMR” present method may be useful for determination derivatives,
and preparation of optklly
method am under study.
of absolute configurations
(Figure 3). The
of various natural products and their
active secondary alcohols. Further versatility and limitation of this new
602
-0.10 .
-0.06 ’
33 +0.06
Y
_rK”q )I;
-0.15orO +0.04
,-. #Ta
12
R = H, MNCB,
MBNC
Figure 3.
A6 values in 13C NMR obtained for the MNCB and MBNC esters of some secondary alcohols. The values in the parentheses are A6 of MBNClOb esters. Border plane is shown by a dotted line.
AcknowledP~
The authors thank Prof. Sotaro Miyano of Tohoku University for valuable advices and
encouragement, REFERENCES
1.
2. 3. 4. 5.
and Dr. Jun Kawabata of their Faculty for help in NMR measurements.
AND NOTES
(a) Parker D. Chem.Rev. 1991,91, 1441-1457. (b) Takeuchi Y.;Itoh N.;Kawahara S.;Koizumi T. Tetrahedron 1993, 49, l&%61-1870. (c) Trost B. M.;Godleski S.;Belletne J. L;McDougal P.G.; Balkovec J.M. J.Org.Chem. 1986, 51, 2370-2374. Dale J.A.;Mosher
H.S. J-Am. Chem.Soc.
Ohtani I.;Kusumi
T.;Kashman
1973,
Y.;Kakisawa
9.5, 512-519.
H. ibid. 1991, 113, 4092-4096.
Miyano S.;Okada S.;Hotta H.;Takeda M.;Suzuki T.;Kabuto 62, 3886-3891.
C.;Yasuhara F. BuN.Chem.Soc.Jpn.
1989,
Suzuki T.;Hotta H.;Hattori T.;Miyano S. Chem. Letf. 1990, 807-808. which is used in the present method, was suggested in this paper.
The same correlation,
6.
Hotta H.;Suzuki T.;Miyano S. ibid.
7.
Miyano S.;Okada S.;Hotta H.;Takeda M.;Kabuto C.; Hashimoto H. BuLl.Chem.Soc.Jpn.
1990,
143-144. 1989,
62,
1528-1533. (aR)-MNCB : mp 187.0-189.O”C, [alz7B +63.5” (c 1.92, CHC13), 1~ NMR (CDC13) &r~s(pprn) ; 3.76(3H,s), 7.05(1H,m), 7.25-7.35(3H,m), 7.74(1H,d,J=2.2Hz), 7.83(1H,m), 7.91(1H,d,J=Y.OHz), 7.97(1H,dd=2.2Hz). (aS)-MNCB : [a]“D -64.2” (c 2.00, CHCU). 8.
The descriptors (aR) and (a9 ) refer to axial chirality.
9.
Hassner A.;Alexanian
V. Tetrahedron Lett. 1978, 44754478.
10.
(a> A JEOL EX 270 and a Bruker AM-500 spectrometers were used to record LH and 13C NMR spectra in CDC13 (ambient temperature). Proton and carbon chemical shifts were determined in 6 units relative to TMS and CDC13, respectively. (b) AS(ppm)=GaR - ha.9 was used for MBNC esters,
II.
Kanger T.;Lopp M.;Miiraus A.;Lijhmus M.;Kobzar G.;Pehk T.; Lille 0. Synthesis 1992, In this paper, O- methylmandelates were used in 13C NMR for the same purpose.
(Received in Japan 16 September 1993; accepted 4 November 1993)
925927.
A NEW MEXHOD FOR ESTABLISHMENT OF ABSOLUTE CONFIGURATIONS OF SECONDARY ALCOHOLS BY NMR SPECTROSCOPY
Yukiharu Fukushi*,
Cbie Yajima and Juaya Mizutani
Departmentof Applied Bioscience, Faculty of Agriculture,HokkaidoUniversity, Kita-ku, Sapporo 060, Japan
Abstrnet : Axially chiral T-methoxy-i,l’-binaphtbyl-Z- carboxylicackt{MBNC, 2) aad Z-(~-metboxy-i’-naphthyl~ 3,5-dichlorobenzoicacid (MNCB, 3) were uscd as chiml derivatiziig agents to determineabsolute ~onfigumtionsof secondaryalcohols by 1~ and 1% NMR spectroscopy.
Recently cwfigurations
a number
of chiml derivatizing
and entmtiomtziic purities
C-centrochirdlity,
agents have been developed
of optically
active mmpoundsl.
for feting
Almost
and among of them, Mosher’s a-methoxy-u-trifluoromethyhylphenylaoetic
absolute
all of them possess acid (MTF’A, 1) has
been most widely used2. “Modified Masher’s method”, a modem variation of Masher’s (lH) method improved by Ohtani et al., is applicable to general secondary alcohols except sterically hindered ones3. On the other hand, Miyano ti al. pointed out the utility of axially chiml 2’-methoxy-l,l’-binaphthyl-2~r~xylic as derivatizing agent for dis~~ation
acid (MBNC, 2)
of emmtiomeric alcohols and amines by ‘H NMR with the aid of
Eu(fod)J”, We estimated dichlorobenzoic
that
axially
chiral
carboxylic
acids
like
2
and
2-(2’-methoxy-l’-naphthyl)-3,5-
acid (MNCB, 3) would be more versatile agents than MlTA
for Musher’s (lH) method.
Enantiomers of 2 were prepared by a known method 5. Racemic 3 was prepared following the procedure of Hotta ef al.“, and derivatized into d~~tereome~c esters of (~}-l-~~nethoI silica-gel column chromatography.
which were separatedeach other by
Purified diastereomers were respectively hydrolyzed by alkali to yield (&)-
and +1&‘)-3~.Various secondary alcohols (4-16) were esterified with (I@- and (a‘Q8-2, and (a@- and (sS)-3 by DCC and 4-pyrrolidinopyridine9.
On the basis of ‘H NMR analyses of the respective diastereomers and the
X-ray crystallographic
data of (a.S)- 2 ester of (-)-mentho17, we devised a new method that could predict the
absolute ~)~igurations
of the chiml secondary alcohols ~cluding sterimlly hindered ones. The basic concept of
this method is essentially the same as that uf “modified Musher’s methud”. For explanation of this method, hereinafter MNI3B esters m used. The idealized conformation
of MNCB
esters is depicted in Figure 1A. 1) The carbinyl proton, ester carbonyl and benzene ring of MNCB moiety lie in the same plane, and the alcohol moiety is neaf the naphthalene ring. 2) The naphthalene and the benz.ene rings of MNCB moiety are orthogonal. For convenience, the plane containing the benzene ring and the conformation of the MNCB group are named tbe CB plane and the ideal ~nfo~tion,
respectively. Due to the d&magnetic
effect of the naphthalene ring, the Ha, Ha’, Hb and Hb’ NMR signals of MNCB ester should appear upfield relative to those of the original alcohol, and also the Ha signal of the (aR)-MNCB ester should appear upfield 599
Hb
Ha
(aS)-MNCE
Hb
estar
(a&MNc8
astar
Figure 1. (A) Cmfigurdtimal correlation mode1 for the (aS)-MNCB
derivatives. CB and border planes are shown. Ha and Hb are on the left and right sides of the CB plane, respectively. Ha’, Hb’ and catbitryl proton are under the border plane. (B) and (C) Views of the (aS)- and (aR)-MNCE esters drown from the direction shown by the outlined arrow in (A).
relative to that of the (as)-MNCB
ester. The reverse should hold true for Hb (Figure 1B). Therefore, when chemical shift difference is defined as Ali(ppm)=GaF - 8&t@, protons on the left side of the CB plane must have positive values (A&O) and protons on the right side of the plane must have negative values (A&CO). The principle is illustrated in Sgure
1B and 1C. The plane, which contains
1’ and 8’ carbons of the naphthakne
ring and the alkoxy oxygen, is drawn with a dotted line in Figure lA-C, This plane is named the border plane. A8 values of the protons under the border plane (Ha’, Hb’ and the carbinyi) am unpredictable, because these protons are strongly irreguk
affected by a fine deviation from the ideal conformation.
However
the signs of AhBof
protons are apt to be the same as that of the car-vinyl proton‘s 116. When these conditions
model A will indicate the correct absolute configuration
are satisfied,
of the compound in question.
As an example, (-)-menthol derivatives (16) can be used to demonstrate the validity of the present method (Figure 2 and Table 1). It is evident that the individual proton signal of the alcohol moieties of MNCB esters appears in upper field than the corresponding one of the original alcohol except the carbinyi proton. Especially, 2fi proton signals of (aS)- and (a@MNCB esters appear at 0.13 and -0.23ppm, respectively. The protons with Ab>O am located on the left side of the CB plane and the ones with AS<0 on the right side. Also, A& values ate infhtenced by the distance between the protons and the ~hth~ene ring. Cto methyl protons, which may be under the border plane (16’), show positive A6 value but the sign is the same as that of the carbinyl proton. This correlation also holds in MBNC esters (4, MBNC esters of (-)-menthol was determined.
9, 16) in Figure 2. By comparison
in ‘H MNR (Table l), the absolute configuration
between
of each enantiomer
MNCB and of MNCB
601
Table
1. lH NMR Data of (-)-Menthol and its MNCB and MBNC Esters {16).
Position
1
2a
R=H MNCEl(aR) (as) MBNC(aS) laRl
1.42 1.16 1.22 1.18 1.26
1.96 1.26 1.48 1.34 1.62
2% 0.95 -0.23 0.13 -0.23 0.24
3
4
5a
3.41 4.40 4.44 4.48 4.52
1.11 0.63 0.41 0.68 0.44
0.99 0.78 0.77 0.82 0.80
5% 1.61 1.43 1.39 1.44 1.40
6a 1.66 1.47 1.49 1.50 1.53
6% 0.84 0.52 0.54 0.54 0.58
7 0.93 0.64 0.73 0.64 0.76
9
8 2.17 1.33 1.11 1.45 1.12
0.91 0.68 0.50 0.71 0.48
10 0.81 0.42 0.46 0.49 0.47
R = ii,YNCB, MBNC
Figure 2 A6 values in 1H: NMR obtained for the MNCB and MBNC esters of secondary alcohols. The values in the parentheses are A& of MBNClob esters. Border planes are shown by dotted lines. For consistency, the results have been transposed to one enantiomer of alcohol (ex. (a.S, R ) = (al?, S)). 16' shows possible ~~~atio~ of 16 (R = MNCB and MBNC). This method is applicable to sterically hindered alcohols (12, 14), and iu t3C NMR” present method may be useful for determination derivatives,
and preparation of optklly
method am under study.
of absolute configurations
(Figure 3). The
of various natural products and their
active secondary alcohols. Further versatility and limitation of this new
602
-0.10 .
-0.06 ’
33 +0.06
Y
_rK”q )I;
-0.15orO +0.04
,-. #Ta
12
R = H, MNCB,
MBNC
Figure 3.
A6 values in 13C NMR obtained for the MNCB and MBNC esters of some secondary alcohols. The values in the parentheses are A6 of MBNClOb esters. Border plane is shown by a dotted line.
AcknowledP~
The authors thank Prof. Sotaro Miyano of Tohoku University for valuable advices and
encouragement, REFERENCES
1.
2. 3. 4. 5.
and Dr. Jun Kawabata of their Faculty for help in NMR measurements.
AND NOTES
(a) Parker D. Chem.Rev. 1991,91, 1441-1457. (b) Takeuchi Y.;Itoh N.;Kawahara S.;Koizumi T. Tetrahedron 1993, 49, l&%61-1870. (c) Trost B. M.;Godleski S.;Belletne J. L;McDougal P.G.; Balkovec J.M. J.Org.Chem. 1986, 51, 2370-2374. Dale J.A.;Mosher
H.S. J-Am. Chem.Soc.
Ohtani I.;Kusumi
T.;Kashman
1973,
Y.;Kakisawa
9.5, 512-519.
H. ibid. 1991, 113, 4092-4096.
Miyano S.;Okada S.;Hotta H.;Takeda M.;Suzuki T.;Kabuto 62, 3886-3891.
C.;Yasuhara F. BuN.Chem.Soc.Jpn.
1989,
Suzuki T.;Hotta H.;Hattori T.;Miyano S. Chem. Letf. 1990, 807-808. which is used in the present method, was suggested in this paper.
The same correlation,
6.
Hotta H.;Suzuki T.;Miyano S. ibid.
7.
Miyano S.;Okada S.;Hotta H.;Takeda M.;Kabuto C.; Hashimoto H. BuLl.Chem.Soc.Jpn.
1990,
143-144. 1989,
62,
1528-1533. (aR)-MNCB : mp 187.0-189.O”C, [alz7B +63.5” (c 1.92, CHC13), 1~ NMR (CDC13) &r~s(pprn) ; 3.76(3H,s), 7.05(1H,m), 7.25-7.35(3H,m), 7.74(1H,d,J=2.2Hz), 7.83(1H,m), 7.91(1H,d,J=Y.OHz), 7.97(1H,dd=2.2Hz). (aS)-MNCB : [a]“D -64.2” (c 2.00, CHCU). 8.
The descriptors (aR) and (a9 ) refer to axial chirality.
9.
Hassner A.;Alexanian
V. Tetrahedron Lett. 1978, 44754478.
10.
(a> A JEOL EX 270 and a Bruker AM-500 spectrometers were used to record LH and 13C NMR spectra in CDC13 (ambient temperature). Proton and carbon chemical shifts were determined in 6 units relative to TMS and CDC13, respectively. (b) AS(ppm)=GaR - ha.9 was used for MBNC esters,
II.
Kanger T.;Lopp M.;Miiraus A.;Lijhmus M.;Kobzar G.;Pehk T.; Lille 0. Synthesis 1992, In this paper, O- methylmandelates were used in 13C NMR for the same purpose.
(Received in Japan 16 September 1993; accepted 4 November 1993)
925927.